Office‐Based Blue Laser Therapy for Vocal Fold Leukoplakia: A Preliminary Report of 12 Cases

Abstract Objective To report the efficacy of office‐based blue laser therapy for vocal fold leukoplakia. Study Design A retrospective case series. Setting A tertiary care center. Methods A retrospective chart review of patients with vocal fold leukoplakia who underwent office‐based blue laser therapy between July 2019 and October 2022 was conducted. The video recordings of their laryngeal examination and their voice evaluation were analyzed before and after surgical intervention. Results A total of 10 patients, eight with unilateral disease and 2 with bilateral disease, were included in this study. In total, 12 vocal folds with leukoplakia were treated. Nine had a single session and 3 had 2 sessions due to incomplete regression of the lesion after the first laser therapy session. Following treatment, 9 regressed completely (75%) and 3 regressed partially (25%). The mean Voice Handicap Index‐10 (VHI‐10) score decreased significantly from 15.4 ± 12.9 preoperatively to 3.8 ± 2.86 after surgery (p = .023). There was a statistically significant decrease in the means of grade, roughness, breathiness, asthenia, and strain (p < .05). There was also a statistically significant decrease in the jitter and shimmer percent (p = .008 and p = .048, respectively) and a significant increase in the maximum phonation time from 9.63 ± 3.83 to 13.54 ± 5.92 seconds (p = .039). Conclusion This preliminary study indicates that office‐based blue laser therapy is an effective treatment modality for vocal fold leukoplakia.

L eukoplakia is defined as a whitish discoloration of the mucosal lining. 1 Its occurrence in the upper aerodigestive system has been associated with several risk factors most important of which are smoking, laryngopharyngeal reflux disease, and genetic predisposition. 2,3 When the vocal fold is affected, leukoplakia invariably denotes a pathologic transformation of the underlying mucosal cover. The pathologic changes can range from epithelial hyperplasia to dysplasia and carcinoma. The prevalence of dysplasia varies with an average occurrence of 50%. [4][5][6] Its presence is usually alarming given the unpredictable course of the disease and the high rate of malignant transformation. In a review of 940 cases, Weller et al reported malignant transformation in 14% within a mean follow-up period of 5.8 years. 7 Several treatment modalities for vocal fold leukoplakia have been suggested. These include vocal hygiene therapy with behavioral modification, 8 frequent biopsies/serial excision, 9 and laser ablation. In 2015, Zhang et al compared the efficacy of carbon dioxide (CO 2 ) laser versus conventional laryngeal microsurgery in the treatment of vocal fold polyps and leukoplakia. Using subjective (Grade, Roughness, Breathiness, Asthenia, and Strain [GRBAS], Voice Handicap Index-10 [VHI-10]) and objective voice measures (acoustic spectrum analysis), the authors showed a better recovery in the laser group compared to the conventional group, especially in patients with vocal fold leukoplakia. 10 Similarly, in 2018, Lim et al reported the use of the CO 2 laser and angiolytic lasers (potassium titanyl phosphate [KTP] and pulse dye laser [PDL]) in the treatment of vocal fold leukoplakia under general anesthesia. Only 1 out of 5 had disease recurrence and the angiolytic laser-stripping group had better voice preservation compared to the CO 2 laser treatment group. 11 With the advances in technology, laser therapy for vocal fold leukoplakia is now being performed in office. The most used lasers are the photoangiolytic lasers, namely the PDL with a wavelength of 583 nm and the KTP laser with a wavelength of 532 nm. [12][13][14] Recently, a new laser with a wavelength of 445 nm (blue laser) has been approved by the Food and Drug Administration and is commonly used as a substitute for the KTP laser. Its hybrid properties, cutting, and coagulation, have increased its versatility in the treatment of different laryngeal pathology. The application of blue laser in the management of vocal fold leukoplakia has been reported only in isolated cases. [15][16][17] Miller et al reported their experience with the blue laser in 29 patients, 4 of whom had suspicious lesions for which laser-assisted diagnostic biopsy was performed. The authors did not elaborate on the pathology of these lesions. 16 Hamdan et al in their series of 11 patients who underwent office-based blue laser therapy described one case of vocal fold leukoplakia that regressed completely following a single treatment session, and another case of carcinoma in situ, which needed radiation therapy. 17 Given the scarcity of reports on office-based blue laser therapy, the authors of this manuscript report their experience with the use of blue laser in 12 cases of vocal fold leukoplakia treated in-office.

Materials and Methods
This study was conducted according to the Declaration of Helsinki and obtained approval from the Institutional Review Board of the American University of Beirut Medical Center (IRB ID: BIO-2022-0280). A retrospective chart review of patients with vocal fold leukoplakia who underwent office-based biopsy followed by blue laser therapy between July 2019 and October 2022 was conducted. The patients included in this review have not been previously reported or included in any prior publication.
Demographic data included age, gender, smoking history, laterality of the lesion (right vs left), size (less than or greater than half the vocal fold), and pathology. A comprehensive voice evaluation was performed before and after surgical intervention. It comprised the VHI-10 described by Rosen et al, 18 GRBAS grading described by Hirano et al, 19 and acoustic analysis using the VISI-PITCH IV software (model 3950B; Kay Pentax). The maximum phonation time (MPT) was also reported as an aerodynamic measure. The acoustic analysis included the fundamental frequency (F 0 ), habitual pitch (HP), percent shimmer, percent jitter, noise-to-harmonic ratio (NHR), and voice turbulence index (VTI). The extent of disease regression seen on laryngeal endoscopy was assessed before and after surgery over a follow-up period that extended from 3 to 14 months. Laryngeal videostroboscopic examinations were also analyzed when available looking at glottic closure and malleability of the vocal fold cover.
The video recordings were reviewed by 2 otolaryngologists independently who rated disease regression following laser therapy. The inter-rater variability was computed to assess the reliability of the reported findings.

Statistical Method
Categorical and continuous variables were described using frequencies and means (±standard deviation), respectively. Using the Statistical Package for the Social Sciences (SPSS) version 24 software package, paired t test was used to analyze continuous variables before and after the intervention. A 2-tailed p < .05 was considered statistically significant.

Surgical Technique
With the patient fully awake and in the upright sitting position, sponges soaked with 1% lidocaine hydrochloride (HCL) and 1:100,000 Epinephrine were inserted and kept in both nasal cavities for 10 minutes to achieve local anesthesia and decongestion. Xylocaine spray (2%) was used (2-3 puffs) to anesthetize the oropharynx and hypopharynx. Laryngeal anesthesia was achieved using the "laryngeal gargle" technique described by Hogikyan. 20 The flexible nasopharyngoscope (Pentax Medical FNL-15RP3) with a working channel was introduced through the nasal cavity to the oropharynx and hypopharynx, and 2 ccs of 4% lidocaine were dripped through the working channel of the endoscope while the patient was asked to sustain the vowel /eh/. Following the application of local anesthesia to the laryngopharyngeal complex, a 400-μm glass fiber was introduced through the working channel and directed toward the site of the lesion. The blue laser (TrueBlue; A.R.C. Laser Company) was administered in the pulse mode using the following set-up: 10 W power, 30 ms pulse duration, and 300 ms interpulse duration. The laser was used in the near-contact and contact modes (see Figures 1 and 2). The tip of the fiber was used at times to curette the surgical debris after laser therapy. All procedures were well-tolerated by the patients.

Demographic Data
A total of 10 patients, eight with unilateral disease and 2 with bilateral disease were included in this study. This study group has not been reviewed or included in previous studies. In total, 12 vocal folds with leukoplakia were treated. The mean age of the study group was 64.8 ± 10.3 years. The male-to-female ratio was 7:3. All patients included in this study were smokers. The majority of the lesions occupied less than half the vocal folds (n = 8) and the most common pathology was lowgrade dysplasia (n = 5). All patients had a single procedure except for 2 patients who underwent 2 procedures each (see Table 1).

Disease Regression After Office-Based Blue Laser Therapy
All patients tolerated well office-based blue laser surgery with no complications noted. The average duration of surgery was 7.16 ± 2.84 minutes with a range from 1.87 to 13.07 minutes. The average amount of joules delivered during surgery which was noted in 5 of the 10 patients was 147.2 ± 88.2 J. The mean follow-up period of the study group was 9 ± 4.03 months, with a range of 3 to 14 months. Out of the 12 vocal fold lesions treated, eight regressed completely (67%) and 4 regressed partially (33%) after a single session of laser therapy. Of those 4 lesions, 3 were treated with another session of officebased blue laser therapy following which there was complete regression in 1 and partial regression in 2. In total, after completion of office-based laser therapy, 9 of the 12 regressed completely (75%) and 3 regressed partially (25%) (see Figure 3). Laryngeal videostroboscopic examinations pre-and postsurgery were available in 7 patients. A review of these video recordings showed improvement in the mucosal waves and better glottic closure after surgery in all patients (see Figure 4).
Inter-rater reliability analysis revealed an intraclass correlation coefficient (ICC) of 0.837 indicating excellent reliability between the 2 otolaryngologists who evaluated the endoscopic laryngeal findings.

VHI-10 and GRBAS Scores Before and After Laser Therapy
The mean VHI-10 score of the total group decreased significantly from 15.4 ± 12.9 preoperatively to 3.8 ± 2.86    Table 2).

Acoustic and Aerodynamic Analysis Before and After Surgery
There was a statistically significant decrease in the jitter percent from 1.27 ± 0.52 preoperatively to 0.72 ± 0.16 postoperatively (p = .008), and in the shimmer percent value from 4.13 ± 1.84 to 2.55 ± 0.89 (p = .048). The decrease in NHR from 0.135 ± 0.03 to 0.12 ± 0.02 and the decrease in VTI from 0.048 ± 0.018 to 0.039 ± 0.009 were not significant (p = .091 and p = .299, respectively) (see Table 3). The mean fundamental frequencies and habitual pitch of the study group before and after surgery, stratified by gender are displayed in Table 4.
With respect to the aerodynamic analysis, there was a significant increase in the MPT from 9.63 ± 3.83 to 13.54 ± 5.92 seconds (p = .039).

Discussion
The last 2 decades witnessed a shift in laryngeal surgery from the operating room to the office. This shift is ascribed mostly to the introduction of the flexible endoscope with a working channel and fiber-based lasers. The ability to deliver laser via a glass fiber has allowed laryngologists to treat benign and per-malignant lesions of the vocal folds under local anesthesia. There are numerous reports in the literature on the use of photoangiolytic lasers in the management of vocal fold leukoplakia/dysplasia, mostly using the PDL or KTP laser. procedures. The authors noted complete disease regression in 41.3% and partial disease regression in 54.4% of the patients. Twenty-eight percent of those who had partial disease regression underwent further surgical intervention in the operating room, 2 of whom were followed by irradiation. 21 In 2017, Hu et al evaluated the feasibility and limitations of office-based CO 2 laser surgery for a variety of laryngeal lesions that included 13 cases of vocal fold leukoplakia. Of the 11 cases who underwent surgery, 9 had complete remission, while 2 had disease recurrence in the subglottic region of the larynx. 22 There is no case series on the use of blue laser for the treatment of vocal fold leukoplakia in an office setting. The results of our study are in alignment with previous reports using other types of lasers. Three out of 4 patients in our study group had complete disease regression and one-third had partial disease regression following officebased blue laser therapy. The disease regression was associated with improvement in both subjective and objective voice outcome measures. There was a significant decrease in the VHI-10 and GRBAS scores, and a significant decrease in the jitter and shimmer percent after treatment. There was also a significant increase in MPT commensurate with improvement in glottic closure during phonation seen in the majority of the cases. The response to treatment can be ascribed to the great affinity of the blue laser for oxyhemoglobin, which allows angiolysis of the sublesional microvasculature thus leading to disease regression. 23 Using electron microscopic examination, Zeitels et al noted denaturation of the basement membrane with separation of the epithelial lining and destruction of the intraepithelial desmosome junctions following KTP laser therapy. 23 These changes were primarily ascribed to selective photo-angiolysis of the subepithelial microvasculature.
This study has its limitations. One is its retrospective nature, which allows for the inherent bias in patient selection as most of the lesions treated (8 of 12) did not exceed half the vocal fold. Patients with bigger lesions would probably have less favorable outcomes than those with smaller lesions as a result of less tolerance as reported by Zheng et al. 24 Second is the relatively small number of subjects which may underpower this study. Another limitation is the short follow-up period in some patients which does not allow us to evaluate the recurrence of disease.

Conclusion
This is the first case series on office-based blue laser therapy for vocal fold with leukoplakia. The results of this preliminary report indicate that blue laser therapy leads to disease regression and improvement in subjective and  objective voice measures in most cases. In-office blue laser therapy may be considered as an effective treatment modality with diligent observation for the need for more than 1 laser session in some cases.